WO2017071607A1 - 4H-吡唑并[1,5-α]苯并咪唑类化合物晶型及其制备方法和中间体 - Google Patents

4H-吡唑并[1,5-α]苯并咪唑类化合物晶型及其制备方法和中间体 Download PDF

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WO2017071607A1
WO2017071607A1 PCT/CN2016/103487 CN2016103487W WO2017071607A1 WO 2017071607 A1 WO2017071607 A1 WO 2017071607A1 CN 2016103487 W CN2016103487 W CN 2016103487W WO 2017071607 A1 WO2017071607 A1 WO 2017071607A1
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solvent
water
group
compound
preparation
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PCT/CN2016/103487
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French (fr)
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吴凌云
张鹏
张丽
王峥
陈曙辉
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南京明德新药研发股份有限公司
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Priority to US15/771,845 priority Critical patent/US10399981B2/en
Priority to EP16859042.0A priority patent/EP3369733B1/en
Priority to CN201680064896.7A priority patent/CN108349975B/zh
Priority to ES16859042T priority patent/ES2784826T3/es
Publication of WO2017071607A1 publication Critical patent/WO2017071607A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to Form A of Compound (I) and a process for the preparation thereof, and to the use of Form A as a PDE2 or TNF- ⁇ inhibitor.
  • Phosphodiesterase catalyzes the hydrolysis of cyclized nucleotides cGMP and cAMP, and regulates various physiological responses by controlling the intramolecular concentrations of these two important secondary signaling factors. Cyclization of nucleotides cGMP and cAMP intramolecular Abnormal regulation is the cause of many diseases. Several drugs have been used to improve and treat diseases by inhibiting PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for arthritis caused by psoriasis. There are eleven major classes of phosphodiesterase genes, each of which can express several subtypes. There are more than 100 PDE subtypes in total. Different subtypes have different structures, different tissue distributions, and circularized nuclei. The activities of cGMP and cAMP are also very different, and the physiological functions of regulation are also very different.
  • PDE2 phosphodiesterase can catalyze the hydrolysis of cyclized nucleotides cGMP and cAMP, while cAMP activity is regulated by cGMP, which plays a key role in the balance of cGMP and cAMP functions in cells.
  • PDE2 is widely expressed in human tissues and is mainly distributed in the heart, central nervous system, liver, adrenal gland, endothelial cells, and platelets. PDE2 is involved in the regulation of various physiological activities, such as central learning, memory and cognition, maintaining the basic rhythm of the heart, smooth muscle and endothelial cells, permeability of endothelial cells, and regulating inflammation. PDE2 knockout mice directly cause embryonic death.
  • PDE2 activity is clinically approved for lower limb paralysis caused by peripheral vascular occlusion. The main role is to reduce blood viscosity, increase red blood cell deformation, and inhibit platelet aggregation. Novel highly selective PDE2 inhibitors have also been reported to control endothelial cell division and angiogenesis, and to improve central cognitive impairment.
  • the development and application of the new novel selective PDE2 inhibitors are still very limited, and the discovery and application of new PDE2 inhibitors have broad prospects.
  • TNF- ⁇ Tumor necrosis factor alpha
  • IL-1 interleukon-1
  • IL-6 proinflammatory cytokines
  • IMID immune-mediated inflammatory diseases
  • RA rheumatoid arthritis
  • psoriatic arthritis psoriatic arthritis
  • JCA juvenile chronic arthritis
  • TNF- ⁇ inhibitors neutralize TNF- ⁇ by TNF- ⁇ inhibitors.
  • TNF- ⁇ monoclonal antibody has been clinically proven to inhibit TNF- ⁇ and is very effective in treating these inflammations.
  • PDE2 can regulate the expression of TNF- ⁇ in a mechanism, so that the level of TNF- ⁇ can be controlled by regulating PDE2 activity, thereby controlling inflammatory response.
  • the present invention provides the crystal form A of the compound (I), and its XRPD pattern is shown in FIG.
  • the XRPD pattern analysis data for Form A is shown in Table 1.
  • Table 1 XRPD pattern analysis data for Form A
  • the method for preparing the above Form A comprises adding a compound of the formula (I) in any form to a solvent of a lipid, an alcohol solvent, acetonitrile, acetone, or a mixed solvent of an alcohol solvent and water.
  • the medium is heated and dissolved, and then cooled and crystallized to obtain.
  • the heating and dissolving further comprises a concentration step of concentrating the solvent to 1/30 to 1/2 of the original volume.
  • the heating and dissolving further comprises a concentration step of concentrating the solvent to 1/20 to 1/5 of the original volume.
  • the weight ratio of the above compound (I) to the solvent is selected from 10 to 1:1.
  • the weight ratio of the above compound (I) to the solvent is selected from 6 to 3:1.
  • the weight ratio of the above compound (I) to the solvent is selected from 5 to 4:1.
  • the heating temperature is selected from the group consisting of 40 ° C to reflux temperature.
  • the heating temperature is selected from the group consisting of 50 ° C to 60 ° C.
  • the temperature-lowering crystallization temperature is selected from 0 ° C to 30 ° C.
  • the temperature-lowering crystallization temperature is selected from the group consisting of 20 ° C to 30 ° C.
  • the lipid solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, and propyl acetate.
  • the lipid solvent is selected from the group consisting of ethyl acetate.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol or tert-butanol.
  • the mixed solvent of the above alcohol solvent and water is selected from the group consisting of methanol/water, ethanol/water, and isopropanol/water.
  • the volume ratio of the alcohol to water is selected from 1:0.5 to 1.
  • the volume ratio of the alcohol to water is selected from 1:1.
  • the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of Form A above or a pharmaceutically acceptable carrier therefor.
  • the present invention also provides the use of the above Form A and its composition for the preparation of a medicament for treating a PDE2 inhibitor and a TNF- ⁇ inhibitor-related disease.
  • the invention also provides the use of the above crystalline form A and its composition in the preparation of a medicament for treating liver diseases.
  • the liver disease is selected from the group consisting of steatohepatitis and liver fibrosis.
  • the crystal form of the invention has good stability and is easy to be used for medicine.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • DCM dichloromethane
  • PE petroleum ether
  • EA ethyl acetate
  • DMF N,N-dimethylformamide
  • DMAC N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • EtOAc ethyl acetate
  • tol stands for toluene
  • THF tetrahydrofuran
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • NMP stands for N-methylpyrrolidone
  • 2-METHF stands for 2-methyltetrahydrofuran
  • Bn stands for benzyl
  • Cbz stands for benzyloxycarbonyl and is an amine protecting group
  • Boc stands for t-butylcarbonyl which is an amine protecting group
  • Fmoc fluorenylmethoxycarbonyl and is an amine a protecting group
  • XRPD X-ray powder diffractometer
  • Tube pressure 40kV
  • DSC Differential Scanning Calorimeter
  • a sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing at RT-300 ° C and a heating rate of 10 ° C/min.
  • TGA Thermal Gravimetric Analyzer
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A.
  • Figure 2 is a DSC chart of Form A.
  • Figure 3 is a TGA map of Form A.
  • Lithium tetrahydroaluminum (2.30 g, 61.0 mmol) was slowly added to tetrahydrofuran (60 mL) under nitrogen at 0 ° C, and ethyl 1,4-dioxaspiro[4,5]nonane-8-carboxyl was added dropwise.
  • 1,4-Dioxaspiro[4,5]nonane-8-ylmethyl methanesulfonate (682 mg, 2.72 mmol), 7-(cyclopropylmethyl)-3-methyl-1H- ⁇ -2,6-(3H,7H)-dione (500 mg, 2.27 mmol) and potassium iodide (37.7 mg, 0.227 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (627 mg) , 4.54 mmol), and the reaction was heated to reflux at 130 ° C for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated evaporated evaporated. ) -3-methyl -1H- purine -2,6- (3H, 7H) - dione (1.10g, yellow oil) .MS-ESI calcd for [M + H] + 375, found 375.
  • Step 5 7-(Cyclopropylmethyl)-3-methyl-1-((4-oxocyclohexyl)methyl)-1H-indole-2,6-(3H,7H)-dione
  • Step 6 7-(Cyclopropylmethyl)-1-(((cis)-4-hydroxy-4-methylcyclohexyl)methyl)-3-methyl-1H-indole-2,6 -(3H,7H)-dione
  • EXPERIMENTAL OBJECTIVE To detect the AMP/GMP concentration produced in the reaction system by detecting the AlexaFluor 633 fluorescent dye substituted on the AMP/GMP antibody by fluorescence polarization analysis, and calculate the IC 50 value of the PDE2 phosphodiesterase inhibition of the test compound.
  • buffer solution 10 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 , 0.01% Brij 35, 1 mM DTT, and 1% DMSO.
  • Enzyme Expression of recombinant full-length human PDE2A protein in insect Sf9 cells using baculovirus using N-terminal GST tag
  • the freshly prepared buffer solution was placed in the reaction solution, and then added to the reaction well, and the DMSO solution of the test compound was added through an Echo 550 non-contact nano-sound sonic pipetting system, and then pre-incubated for 10 minutes at room temperature, and the substrate was added (1 ⁇ M).
  • the reaction was initiated by cGMP) and allowed to react at room temperature for one hour. Then join the detection system ( AMP 2 /GMP 2 antibody, AMP2/GMP2 AlexaFluor 633 fluorescent dye), reacted at room temperature for 90 minutes, and then detected fluorescence polarization using Ex/Em 620/688.
  • Fluorescence polarization intensity was converted to nM concentration by AMP/GMP standard curve, then relative enzyme activity inhibition relative to DMSO blank was calculated, and IC50 values and curves were calculated using the Prism software package (GraphPad Software, San Diego California, USA).
  • OBJECTIVE To examine the effects of compounds on the TNF- ⁇ in the blood of rats induced by LPS in vitro, and to evaluate the inhibitory effect of the compounds on LPS-induced TNF- ⁇ in rat blood.
  • Rat TNF-alpha Quantikine ELISA Kit R&D, #SRTA00
  • a test compound solution having a concentration of 1 mM was prepared, and 40 ⁇ L (the final concentration of the compound was 100 uM) was added to a 48-well cell culture plate, respectively.
  • blood was collected from the heart (heparin anticoagulation).
  • Blood was added to a 48-well plate to which the test compound had been added, 320 ⁇ L per well.
  • the 48-well plate was placed in a cell culture incubator, and after 30 minutes of incubation, it was taken out, and 40 ⁇ L of LPS solution (100 ug/ml) was added, mixed, and placed in an incubator to continue incubation.
  • the 48-well plate was taken out, and the blood sample was transferred to a 1.5 ml centrifuge tube, centrifuged in a centrifuge (4,500 rpm, 4 ° C, 5 minutes), and the upper layer was separated for plasma, and then frozen and stored in a -80 degree refrigerator.
  • the R&D ELISA kit was used to detect TNF- ⁇ levels in plasma samples.
  • the compounds of the invention have significant and unexpected TNF- ⁇ inhibitory activity.
  • the rodent pharmacological characteristics of the compound after intravenous injection and oral administration were tested by a standard protocol.
  • the candidate compound was formulated into a clear solution, and the rats were administered a single intravenous injection and oral administration.
  • the intravenous and oral vehicles are a certain proportion of aqueous hydroxypropyl ⁇ -cyclodextrin or physiological saline solution. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times volume of acetonitrile solution containing internal standard to precipitate protein, centrifuge to remove the supernatant, add equal volume of water and centrifuge to remove the supernatant.
  • the LC-MS/MS analysis method was used to quantitatively analyze the plasma concentration, and the pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half-life, area under the curve of the drug, and bioavailability were calculated.
  • Compound (I) can significantly improve the single or partial index of rat pharmacokinetics.
  • the crystal A opening was placed in a constant temperature and humidity container for accelerated test under the conditions of 40 ° C / 75% humidity (open), sampling at 1, 2, and 3 months, and the initial detection on the 0th day.
  • the results were compared and the test results are shown in Table 6 below:

Abstract

本发明公开了化合物(Ⅰ)的晶型A及其制备方法，本发明还公开了晶型A作为PDE2或TNF-α抑制剂的应用。

Description

4H-吡唑并[1,5-α]苯并咪唑类化合物晶型及其制备方法和中间体 技术领域
本发明涉及化合物(Ⅰ)的晶型A及其制备方法，以及晶型A作为PDE2或TNF-α抑制剂的应用。
背景技术
磷酸二酯酶(PDE)催化水解环化核苷酸cGMP和cAMP,通过控制这两个重要的二级信号因子的分子内浓度调控各种生理反应.环化核苷酸cGMP和cAMP分子内的调控异常是导致许多疾病的原因,现在已经有多个药物通过抑制PDE活性来改善和治疗疾病,如PDE5抑制剂用于肺动脉高压,PDE4抑制剂用于银屑病引起的关节炎.目前已知的磷酸二酯酶基因共有十一个大类,每一类又可以表达若干亚型,总共有超过100种PDE亚型.不同的亚型具有不同的结构,不同的组织分布,对环化核苷酸cGMP和cAMP的活性也有很大的不同，调控的生理功能也是千差万别.
PDE2磷酸二酯酶可以催化水解环化核苷酸cGMP和cAMP，同时cAMP活性受cGMP调控，对于细胞内的cGMP和cAMP功能平衡起关键作用。PDE2在人体组织中广泛表达，分布主要是心脏,中枢神经系统,肝脏,肾上腺,内皮细胞,和血小板等。PDE2参与调节各项生理活性,如中枢的学习、记忆和认知等过程，维持心脏,平滑肌和内皮细胞的基本节律,内皮细胞的通透性,调节炎症反应。PDE2基因敲初小鼠直接导致胚胎死亡。通过抑制PDE2活性可能用于各种中枢，心血管疾病，和控制炎症反应。多种天然和合成的嘌呤类化合物的非选择性PDE抑制活性很早就被发现，如咖啡因，茶碱，己酮可可碱等。己酮可可碱(PDE2活性)临床上批准用于周边血管诸塞造成的下肢跛行，主要作用是降低血液粘度，提高红细胞变形，抑制血小板凝聚等。新型的高选择性PDE2抑制剂也有报道用于控制内皮细胞的分裂和血管再生，和改善中枢认知障碍。但总体新型的选择性PDE2抑制剂的开发和应用还非常有限，发现和应用新型PDE2抑制剂具有广阔的前景。
肿瘤坏死因子α(tumor necrosis factor alpha，TNF-α)是一种具有多种生物学活性的细胞因子，对多种疾病特别是免疫和炎症相关的疾病的发生、发展及治疗具有重要影响。TNF-α主要由单核细胞和巨噬细胞系产生，参与机体的免疫调节和细胞因子网络协调。正常情况下，TNF-α对免疫防御和免疫监督起着重要作用，但在某些情况下却有不良作用。研究显示，TNF-α过量表达可诱导促炎细胞因子如白介素1(interleukon-1，IL-1)、IL-6等的表达、增加内皮细胞通透性、上调粘附分子表达、激活中性白细胞和嗜酸细胞，并且诱导骨滑膜细胞和软骨细胞分泌急性期物质和组织降解酶等促进炎症的发生。这些病理反应在许多免疫介导的炎症性疾病(Immune-mediated inflammatory diseases，IMID)的发生发展中起着非常重要的作用，如风湿性关节炎(rheumatoid arthritis，RA)、牛皮癣关节炎(psoriatic arthritis，PsA)、强直性脊椎炎(ankylosing spondylitis，AS)、炎症性肠炎(inflammatory bowel disease，IBD)、幼年型慢性关节炎(juvenile chronic arthritis，JCA)以及脉管炎(vasculitis)等。研究表明，TNF-α是以上多种IMID的理想靶标。同时对于一些由于长期损伤慢性炎症造成的疾病,如脂肪肝炎,慢性阻塞性肺炎等，使 用TNF-α拮抗药物(TNF-αinhibitors)来中和过量的TNF-α，也是有效的防治和治疗途径，TNF-α单抗药物在临床上已经证明抑制TNF-α是非常有效的治疗上述炎症相关疾病的手段。PDE2从机理上可以调控TNF-α的表达，因此可以通过调节PDE2活性了控制TNF-α的水平，从而可以实现控制炎症反应。
发明内容
本发明提供了化合物(Ⅰ)的晶型A，其XRPD图谱如图1所示，
Figure PCTCN2016103487-appb-000001
本发明的一些方案中，晶型A的XRPD图谱解析数据如表1所示。
表1：晶型A的XRPD图谱解析数据
NO. 2-Theta I％ NO. 2-Theta I％
1 9.578 100 16 22.141 31.1
2 10.43 40.1 17 22.928 6.4
3 12.502 18.2 18 23.387 4.4
4 13.996 4 19 24.27 4.6
5 15.086 7.7 20 24.548 39.8
6 15.38 16.5 21 25.116 3
7 16.287 7.4 22 25.834 9.5
8 16.661 6.3 23 26.719 5.3
9 17.428 85.8 24 27.665 3.6
10 17.646 29.8 25 29.477 16
11 18.298 11.3 26 30.956 5.6
12 19.977 10.2 27 32.416 3.4
13 20.427 10.2 28 34.623 3.4
14 20.879 29.7 29 37.243 3.5
15 21.314 8.6 30 39.237 3.6
本发明的一些方案中，上述晶型A的制备方法，包括将任意一种形式的式化合物(Ⅰ)加入到脂类溶剂、醇类溶剂、乙腈、丙酮、或醇类溶剂与水的混合溶剂中加热溶解，然后降温析晶制得。
本发明的一些方案中，上述加热溶解后还包括浓缩步骤，将溶剂浓缩至原体积的1/30～1/2。
本发明的一些方案中，上述加热溶解后还包括浓缩步骤，将溶剂浓缩至原体积的1/20～1/5。
本发明的一些方案中，上述化合物(Ⅰ)与溶剂的重量比选自10～1:1。
本发明的一些方案中，上述化合物(Ⅰ)与溶剂的重量比选自6～3:1。
本发明的一些方案中，上述化合物(Ⅰ)与溶剂的重量比选自5～4:1。
本发明的一些方案中，上述加热温度选自40℃～回流温度。
本发明的一些方案中，上述加热温度选自50℃～60℃。
本发明的一些方案中，上述降温析晶温度选自0℃～30℃。
本发明的一些方案中，上述降温析晶温度选自20℃～30℃。
本发明的一些方案中，上述脂类溶剂选自乙酸乙酯、乙酸异丙酯、乙酸丙酯。
本发明的一些方案中，上述脂类溶剂选自乙酸乙酯。
本发明的一些方案中，上述醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇。
本发明的一些方案中，上述醇类溶剂与水的混合溶剂选自甲醇/水、乙醇/水、异丙醇/水。
本发明的一些方案中，上述醇与水的体积比选自1:0.5～1。
本发明的一些方案中，上述醇与水的体积比选自1:1
本发明还提供了一种药物组合物，其含有治疗有效量的上述晶型A或其药学上可接受的载体。
本发明还提供了上述晶型A及其组合物在制备治疗PDE2抑制剂和TNF-α抑制剂相关疾病药物中的应用。
本发明还提供了上述晶型A及其组合物在制备治疗肝类疾病药物中的应用。
本发明的一些方案中，上述肝类疾病选自脂肪性肝炎和肝纤维化。
本发明的晶型稳定性好，易于成药。
定义和说明：
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的(Protective Groups In Organic Synthesis,Wiley and Sons,1991)是这方面的权威。本发明引用的所有参考文献整体上并入本发明。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶 剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词：DCM代表二氯甲烷；PE代表石油醚；EA代表乙酸乙酯；DMF代表N,N-二甲基甲酰胺；DMAC代表N,N-二甲基乙酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；tol代表甲苯；THF代表四氢呋喃；EtOH代表乙醇；MeOH代表甲醇；NMP代表N-甲基吡咯烷酮；2-METHF代表2-甲基四氢呋喃；i-PrOH代表2-丙醇；Bn代表苄基；Cbz代表苄氧羰基，是一种胺保护基团；Boc代表叔丁基羰基是一种胺保护基团；Fmoc代表笏甲氧羰基，是一种胺保护基团；Alloc代表烯丙氧羰基，是一种胺保护基团；Teoc代表三甲基硅乙氧羰基，是一种胺保护基团；Boc2O代表二-叔丁基二碳酸酯；HCl(g)代表氯化氢气体；H2SO4代表硫酸；HOAc代表乙酸；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；DIEA代表二异丙基乙基胺；NMM代表N-甲基吗啡啉；DBU代表1,8-二氮杂二环十一碳-7-烯；Et3N代表三乙胺；LDA代表二异丙基胺锂；NaHMDS代表双(三甲基硅基)氨基钠；KHMDS代表双(三甲基硅基)氨基钾；LiAlH4代表四氢铝锂；t-BuOK代表叔丁醇钾；H2O2代表过氧化氢；NH4Cl代表氯化铵；BaSO4代表硫酸钡；CaCO3代表碳酸钙；SnCl2代表氯化亚锡；Zn(BH4)2代表硼氢化锌；PPh3代表三苯基膦；HMDS代表六甲基二硅胺烷；Pd/C代表钯碳；PtO2代表二氧化铂；Pd(OH)2代表氢氧化钯；Pd2(dba)3代表三(二亚苄基丙酮)二钯；Pd(PPh3)4代表四三苯基膦钯；Pd(dppf)Cl2代表1,1'-双(二苯基磷)二茂铁氯化钯；Pd(PPh3)2Cl2代表二氯双(三苯基膦)钯(II)；Pd(OAc)2代表醋酸钯；PdCl2代表氯化钯；CuI代表碘化亚铜；CuBr代表溴化亚铜；CuCl代表氯化亚铜；Cu代表铜粉；Cu2O代表氧化亚铜；Xantphos代表4,5-双(二苯基磷)-9,9-二甲基氧杂蒽；Sphos代表2-二环己基亚膦基-2',6'-二甲氧基联苯；Xphos代表2-二环己基磷-2',4',6'-三异丙基联苯；Ruphos代表2-双环己基膦-2',6'-二异丙氧基-,1,1'-联苯；Brettphos代表2-(二环己基膦基)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯。
化合物经手工或者
Figure PCTCN2016103487-appb-000002
软件命名，市售化合物采用供应商目录名称。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器：Bruker D8ADVANCE X-射线衍射仪；
方法：靶:Cu:K-Alpha；
波长
Figure PCTCN2016103487-appb-000003
管压Voltage:40kV；
管流Current:40mA；扫描范围:4～40°；
样品旋转速度:15rpm；
扫描速度:10°/分钟。
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器：TA Q2000差示扫描量热仪；
方法：取样品(～1mg)置于DSC铝锅内进行测试，方法为：RT-300℃，升温速率10℃/min。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器：TA Q5000热重分析仪；
方法：取样品(2～5mg)置于TGA铂金锅内进行测试，方法为：RT-300℃，升温速率10℃/min。
附图说明
图1为晶型A的Cu-Kα辐射的XRPD谱图。
图2为晶型A的DSC图谱。
图3为晶型A的TGA图谱。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1
7-(环丙基甲基)-1-(((顺式)-4-羟基-4-甲基环己基)甲基)-3-甲基-1H-嘌呤-2,6-(3H，7H)-二酮
Figure PCTCN2016103487-appb-000004
第一步：乙基1，4-二氧杂螺[4,5]癸烷-8-羧酸乙酯
将乙基4-氧代环己烷羧酸(30.0g，176mmol)，乙二醇(22.0g，353mmol)和对甲苯磺酸(304mg，1.70mmol)溶于甲苯(315mL)中，加分水器后加热回流反应过夜。反应液冷却至室温，依次用水(300 mL x 2)、饱和碳酸氢钠(500mL x 2)洗涤，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩，用硅胶柱色谱法分离纯化(1：1石油醚/乙酸乙酯，Rf＝0.3)得到产物乙基1，4-二氧杂螺[4，5]癸烷-8-羧酸乙酯(37.2g，黄色液体)，产率：99％。MS-ESI计算值[M+H]+215，实测值215。
第二步：1,4-二氧杂螺[4，5]癸烷-8-基甲醇
在氮气保护，0℃时下将四氢铝锂(2.30g，61.0mmol)缓慢加入四氢呋喃(60mL)中，滴加乙基1，4-二氧杂螺[4,5]癸烷-8-羧酸乙酯(10.0g，42.0mmol)的四氢呋喃(40mL)溶液。反应缓慢升至25℃，搅拌3.5小时。反应液冷却至0℃，依次缓慢加入水(2.30g，127mmol)，15％氢氧化钠(2.30g，8.60mmol)及水(6.9g，383mmol)。过滤，滤饼用四氢呋喃(50mL x 3)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到产品1,4-二氧杂螺[4,5]癸烷-8-基甲醇(6.22g，黄色液体)，产率：89％。MS-ESI计算值[M+H]+173，实测值173。
第三步：1,4-二氧杂螺[4,5]癸烷-8-基甲基甲磺酸酯
将1,4-二氧杂螺[4,5]癸烷-8-基甲醇(2.00g，12.0mmol)及二异丙基乙基胺(3.10g，24.0mmol)溶于二氯甲烷(40mL)中，在0℃下缓慢加入甲烷磺酰氯(3.90g，30.0mmol)。反应液升至25℃，搅拌过夜。加入饱和氯化铵水溶液(100mL)淬灭反应，用乙酸乙酯萃取(200mL x 3)。合并有机相，用无水硫酸镁干燥，过滤，滤液减压浓缩用硅胶柱色谱法分离纯化(3：1石油醚/乙酸乙酯，Rf＝0.4)，得到产物1,4-二氧杂螺[4,5]癸烷-8-基甲基甲磺酸酯(1.80g，黄色液体)，产率：60％。MS-ESI计算值[M+H]+251，实测值251。
第四步：1-(1,4-二氧杂螺[4,5]癸烷-8-基甲基-7-(环丙基甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮
将1,4-二氧杂螺[4,5]癸烷-8-基甲基甲磺酸酯(682mg，2.72mmol)，7-(环丙基甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮(500mg，2.27mmol)及碘化钾(37.7mg，0.227mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(627mg，4.54mmol)，反应130℃加热回流4小时。反应液冷却至室温，过滤，滤液减压浓缩，得到的粗产品1-(1,4-二氧杂螺[4,5]癸烷-8-基甲基-7-(环丙基甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮(1.10g，黄色油状)。MS-ESI计算值[M+H]+375，实测值375。
第五步：7-(环丙基甲基)-3-甲基-1-((4-氧环己基)甲基)-1H-嘌呤-2,6-(3H,7H)-二酮
将1-(1,4-二氧杂螺[4,5]癸烷-8-基甲基-7-(环丙基甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮(1.20g，2.09mmol)溶于丙酮(12mL)中，加入4N盐酸水溶液(3mL)。反应室温搅拌过夜，加入水(20mL)，用乙酸乙酯(30mL x 3)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到的产品用硅胶 柱色谱法纯化(1：1石油醚/乙酸乙酯，Rf＝0.3)得到产物7-(环丙基甲基)-3-甲基-1-((4-氧环己基)甲基)-1H-嘌呤-2,6-(3H,7H)-二酮(52.0mg，黄色固体)，产率：8％。MS-ESI计算值[M+H]+331，实测值331。
第六步：7-(环丙基甲基)-1-(((顺式)-4-羟基-4-甲基环己基)甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮
将7-(环丙基甲基)-3-甲基-1-((4-氧环己基)甲基)-1H-嘌呤-2,6-(3H,7H)-二酮(100mg，0.303mmol)溶于四氢呋喃(5mL)，-78℃时在氮气保护下缓慢加入甲基格氏试剂(3M乙醚溶液，0.60mL，1.8mmol)，-78℃搅拌半小时，接着0℃反应2小时。缓慢滴加加水(10mL)淬灭反应，反应液用乙酸乙酯(30mL x 3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品用制备高效液相色谱纯化得产物7-(环丙基甲基)-1-(((顺式)-4-羟基-4-甲基环己基)甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮(42.0mg，白色固体)即为化合物(Ⅰ)，产率：40％。1H NMR：(400MHz，Methonal-d4)δ7.99(s，1H)，4.19(d，J＝8.0Hz，2H)，3.89(d，J＝8.0Hz，2H)，3.54(s，3H)，1.81-1.70(m，1H)，1.69-1.62(m，2H)，1.51-1.41(m，4H)，1.39-1.25(m，3H)，1.15(s，3H)，0.63-0.56(m，2H)，0.48-0.42(m，2H)。
MS-ESI计算值[M+H-H2O]+329，实测值329。
第七步：晶型A制备
将7-(环丙基甲基)-1-(((顺式)-4-羟基-4-甲基环己基)甲基)-3-甲基-1H-嘌呤-2,6-(3H,7H)-二酮(42.0mg)加入乙酸乙酯(10mL),加热至50℃溶解。将溶液减压浓缩至0.5mL,析出固体，混合物室温搅拌过夜。将混合物过滤，收集滤饼。将滤饼干真空燥后得晶型A。
实验例1：体外评价PDE2磷酸二酯酶抑制活性
实验目的：通过荧光偏振分析法检测AMP/GMP抗体上取代的AlexaFluor 633荧光染料来检测反应体系中产生的AMP/GMP浓度,计算待测化合物的PDE2磷酸二酯酶抑制IC50值。
实验材料:
测定緩沖溶液:10mM Tris-HCl,pH 7.5,5mM MgCl2,0.01％Brij 35,1mM DTT,and 1％DMSO.
酶:使用N端GST标签用杆状病毒在昆虫Sf9细胞中表达重组全长人PDE2A蛋白
底物:1μM cGMP
检测方法:
Figure PCTCN2016103487-appb-000005
AMP2/GMP2抗体,AMP2/GMP2AlexaFluor 633荧光染料
实验操作:
将新鲜制备的缓冲溶液配置酶溶液，然后加入到反应孔穴中，通过Echo550非接触式纳升级声波 移液系统加入待测化合物的DMSO溶液，然后室温下预温育10分钟，加入底物(1μM cGMP)引发反应，室温反应一小时。然后加入检测系统(
Figure PCTCN2016103487-appb-000006
AMP2/GMP2抗体,AMP2/GMP2AlexaFluor 633荧光染料)，室温下反应90分钟，然后使用Ex/Em 620/688检测荧光偏振。
荧光偏振强度通过AMP/GMP标准曲线换算成nM浓度，然后计算相对DMSO空白的相对酶活性抑制，利用Prism软件包(GraphPad Software,San Diego California,USA)计算IC50值和曲线
实验结果：
表2：PDE2磷酸二酯酶抑制活性测试结果
供试品 PDE2磷酸二酯酶抑制活性
化合物(Ⅰ) ++
注：1μM≦“++”＜10μM。
结论：化合物(Ⅰ)具有显著甚至意料不到的PDE2A蛋白酶抑制活性。
实验例2：体外评价化合物对LPS诱导大鼠血液中TNF-α的影响
实验目的：在体外检测化合物对LPS诱导大鼠血液中TNF-α的影响，评估化合物对大鼠血液中LPS诱导TNF-α的抑制作用。
实验材料:
Sprague Dawley大鼠(雄性,210～260g,8～10周龄，上海斯莱克)
Rat TNF-alpha Quantikine ELISA Kit(R&D,#SRTA00)
实验操作:
配制浓度为1mM的待测化合物溶液，分别在48孔细胞培养板中加入40μL(化合物终浓度为100uM)。大鼠用异氟烷麻醉后，于心脏采血(肝素抗凝)。将血液加入已经加好待测化合物的48孔板中，每孔320μL。将48孔板放置于细胞培养箱中，孵育30分钟后取出，加入40μL LPS溶液(100ug/ml)，混匀后放置于培养箱中继续孵育。5小时后取出48孔板，血样转移至1.5ml离心管中，置于离心机中离心(4,500rpm,4℃,5minutes)，分离上层得血浆，分装后速冻，保存在-80度冰箱。第二天按照试剂盒说明书操作用R&D ELISA试剂盒进行血浆样品中TNF-α水平检测。
实验结果：
表3：TNF-α抑制活性测试结果
供试品 TNF-α抑制比率
化合物(Ⅰ) ++
注：80％≦“++”＜100％。
结论：本发明化合物具有显著甚至意料不到的TNF-α抑制活性。
实验例3：化合物药代动力学评价
实验目的：测试化合物在SD大鼠体内药代动力学
实验材料：Sprague Dawley大鼠(雄性,200-300g,7～9周龄，上海斯莱克)
实验操作：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予大鼠单次静脉注射及口服给药。静注及口服溶媒为一定比例的羟丙基β环糊精水溶液或生理盐水溶液。收集24小时内的全血样品，3000g离心15分钟，分离上清得血浆样品，加入4倍体积含内标的乙腈溶液沉淀蛋白，离心取上清液加入等倍体积的水再离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
实验结果：
表4：药代动力学测试结果
供试品 清除率(mL/min/kg) 半衰期T1/2(h) 浓度积分AUC(nM.hr) 生物利用度F(％)
己酮可可碱 74.1 0.191 6622  
化合物(Ⅰ) 54.4 0.793 4390 47.9
结论：化合物(Ⅰ)可以显著提高大鼠药代动力学单项或部分指标。
实验例4：晶型A在不同溶剂中的溶解度
称取约2mg晶型A到1.5mL的液相小瓶中，分别用移液枪逐级加入如下溶剂，手动振摇溶解。该测试是在室温下进行，通过肉眼来判断溶解情况，结果见表5。
表5：晶型A在不同溶剂中的溶解度
编号 溶剂 溶解度(mg/mL) 编号 溶剂 溶解度(mg/mL)
1 甲醇 ～28.7 14 甲苯 <1.0
2 乙醇 ～11.2 15 正庚烷 <1.0
3 异丙醇 ～10.1 16 环己烷 <1.0
4 正丁醇 ～20.5 17 二氧六环 >57.0
5 乙腈 ～13.0 18 水 <1.0
6 丙酮 ～17.2 19 甲醇-水(1:1) ～7.8
7 丁酮 ～37.2 20 甲醇-水(3:1) ～19.0
8 甲基异丁基酮 ～10.9 21 乙醇-水(1:1) ～16.3
9 乙酸乙酯 ～15.2 22 乙醇-水(3:1) ～24.5
10 醋酸异丙酯 ～12.0 23 乙腈-水(1:1) ～22.2
11 甲基叔丁基醚 ～2.6 24 丙酮-水(1:2) ～1.0
12 四氢呋喃 >67.0 25 异丙醇-水(1:1) ～17.3
13 2-甲基四氢呋喃 ～24.2 - - -
实验例5：晶型A固体稳定性试验
将结晶A开口置于恒温恒湿容器中进行加速试验，条件分别为40℃/75％湿度(敞口)，于第1、2、3个月取样检测，检测结果与第0天的初始检测结果进行比较，试验结果见下表6所示：
表6：晶型A固体稳定性实验
Figure PCTCN2016103487-appb-000007

Claims (10)

  1. 化合物(Ⅰ)的晶型A，其XRPD图谱如图1所示，
    Figure PCTCN2016103487-appb-100001
  2. 根据权利要求1所述晶型A的制备方法，包括将任意一种形式的式化合物(Ⅰ)加入到脂类溶剂、醇类溶剂、乙腈、丙酮、或醇类溶剂与水的混合溶剂中加热溶解，然后降温析晶制得。
  3. 根据权利要求2所述晶型A的制备方法，加热溶解后还包括浓缩步骤，将溶剂浓缩至原体积的1/30～1/2，优选自1/20～1/5。
  4. 根据权利要求2所述晶型A的制备方法，其中，化合物(Ⅰ)与溶剂的重量比选自10～1:1，优选自6～3:1，更优选自5～4:1。
  5. 根据权利要求2所述晶型A的制备方法，其中所述加热温度选自40℃～回流温度，优选自50℃～60℃。
  6. 根据权利要求2所述晶型A的制备方法，其中所述降温析晶温度选自0℃～30℃，优选自20℃～30℃。
  7. 根据权利要求2所述晶型A的制备方法，其中脂类溶剂选自乙酸乙酯、乙酸异丙酯、乙酸丙酯，优选自乙酸乙酯；或
    醇类溶剂选自甲醇、乙醇、异丙醇或叔丁醇；
    醇类溶剂与水的混合溶剂选自甲醇/水、乙醇/水、异丙醇/水，其中，醇与水的体积比选自1:0.5～1，优选自1:1。
  8. 一种药物组合物，其含有治疗有效量的根据权利要求1～7任意一项所述的晶型A或其药学上可接受的载体。
  9. 根据权利要求1～7任意一项所述晶型A或权利要求8所述组合物在制备治疗PDE2抑制剂和TNF-α抑制剂相关疾病药物中的应用。
  10. 根据权利要求1～7任意一项所述晶型A或权利要求8所述组合物在在制备治疗肝类疾病药物中的应用，其中所述肝类疾病选自脂肪肝性肝炎和肝纤维化。
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